Triazolophthalazines

ABSTRACT

The compounds of formula I 
     
       
         
         
             
             
         
       
         
         
           
             in which R1 and R2 have the meanings as given in the description are novel effective PDE2 inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel triazolophthalazine derivatives, whichcan be used in the pharmaceutical industry for the production ofpharmaceutical compositions.

KNOWN TECHNICAL BACKGROUND

Triazolophthalazines are known from prior art. For example, EP85840,WO98/04559, WO98/50385, WO99/06407 (U.S. Pat. No. 6,313,125),WO02/083140, U.S. Pat. No. 6,525,055, EP0728759 (U.S. Pat. No.6,001,830); J. Med. Chem., (1988), 31, 1115-1123; J. Med. Chem., (2004),47, 1807-1822, and J. Med. Chem., (2004), 47, 2176-2179 describetriazolophthalazines with various substitution patterns.

But, however, anilino-substituted triazolophthalazine derivatives in themeaning of the present invention have never been disclosed therein.

Yet however, triazolophthalazine derivatives have never been describedas PDE2-inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the novel triazolophthalazine derivatives,which are described in greater details below, have surprising andparticularly advantageous properties.

The invention thus relates in a first aspect (aspect a) to compounds offormula I

in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, or R11- and/or        R111-substituted phenyl, in which

R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl, 1-4C-alkoxy,completely or predominantly fluorine-substituted 1-4C-alkoxy, phenoxy,1-4C-alkoxycarbonyl, morpholino, or di-1-4C-alkylamino,

-   -   R111 is 1-4C-alkoxy, halogen, hydroxyl, or 1-4C-alkyl,    -   R2 is amino, carboxyl, 1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or        —C(O)—N(R4)R5, in which    -   R3 is 1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl,        trifluoromethyl, phenyl, R31- and/or R311-substituted phenyl,        furanyl, imidazol-4-yl, pyridinyl, R32-substituted 1-4C-alkyl,        or 1N—(R33)-piperidinyl, in which    -   R31 is 1-4C-alkoxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl,        hydroxyl, 1-4C-alkoxycarbonyl, 3-7C-cyloalkylmethoxy,        morpholino, or mono- or di-1-4C-alkylamino,    -   R311 is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or        3-7C-cyloalkylmethoxy,    -   or R31 and R311 together are a 1-2C-alkylenedioxy group,    -   R32 is hydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321-        and/or R3211-substituted phenyl, mono- or di-1-4C-alkylamino,        morpholino, or 4N—(R322)-piperazin-1-yl, in which    -   R321 is 1-4C-alkoxy, halogen, nitro, 1-4C-alkyl,        trifluoromethyl, hydroxyl, 1-4C-alkoxycarbonyl,        3-7C-cyloalkylmethoxy, or mono- or di-1-4C-alkylamino,    -   R3211 is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or        3-7C-cyloalkylmethoxy,    -   or R321 and R3211 together are a 1-2C-alkylenedioxy group,    -   R322 is 1-4C-alkyl,    -   R33 is hydrogen, 1-4C-alkyl, or 1-4C-alkylcarbonyl,    -   R4 is hydrogen, 1-4C-alkyl, R41-substituted 2-4C-alkyl, phenyl,        R42- and/or R421-substituted phenyl, or pyridinyl, in which    -   R41 is hydroxyl, 1-4C-alkoxy, mono- or di-1-4C-alkylamino, or        morpholino,    -   R42 is 1-4C-alkoxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl,        hydroxyl, 1-4C-alkoxycarbonyl, 3-7C-cyloalkylmethoxy, or mono-        or di-1-4C-alkylamino,    -   R421 is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or        3-7C-cyloalkylmethoxy,    -   or R42 and R421 together are a 1-2C-alkylenedioxy group,    -   R5 is hydrogen, or 1-4C-alkyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl,

and the salts of these compounds.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, and, particularly, the ethyl and methyl radicals.

2-4C-Alkyl is a straight-chain or branched alkyl radical having 2 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl and ethyl radicals.

3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclopentyl andcyclohexyl are in particular to be mentioned.

2-4C-Alkenyl is a straight chain or branched alkenyl radical having 2 to4 carbon atoms. Examples are the ethenyl (vinyl), 2-butenyl, 3-butenyl,1-propenyl and the 2-propenyl (allyl) radicals.

Halogen within the meaning of the present invention is iodine or, inparticular, bromine, chlorine or fluorine.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are themethoxycarbonyl (CH₃O—C(O)—) and the ethoxycarbonyl (CH₃CH₂O—C(O)—)radical.

3-7C-Cycloalkylmethoxy stands for cyclopropylmethoxy, cyclobutylmethoxy,cyclopentylmethoxy, cyclohexylmethoxy or cycloheptylmethoxy, of whichcyclopropylmethoxy and cyclopentylmethoxy are to be emphasized.

1-2C-Alkylenedioxy stands, for example, for the methylenedioxy(—O—CH₂—O—) or the ethylenedioxy radical (—O—CH₂—CH₂—O—).

Completely or predominantly fluorine-substituted 1-4C-alkoxy is, forexample, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy,the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxyradical, of which the difluoromethoxy radical is preferred.“Predominantly” in this connection means that more than half of thehydrogen atoms of the 1-4C-alkoxy groups are replaced by fluorine atoms.

Di-1-4C-alkylamino stands for an amino group, which is substituted bytwo different or two identical of the abovementioned 1-4C-alkylradicals. Examples are the dimethylamino, the diethylamino and thediisopropyl radical.

Di-(1-4C-alkoxy)-phenyl stands for a phenyl radical, which issubstituted at any possible positions by two of the abovementioned1-4C-alkoxy radicals, which may be the same or different.

Mono- or Di-1-4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the abovementioned 1-4C-alkyl radicals. Preferredare the di-1-4C-alkylamino radicals, especially the dimethylamino, thediethylamino and the diisopropylamino radical.

Phenyl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals, which is substituted by the phenyl radical. Examples which maybe mentioned are the benzyloxy and the phenethoxy radical.

1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is the acetylradical (CH₃CO—).

The heterocyclic groups mentioned herein refer, unless otherwisementioned, to all of the possible isomeric forms thereof.

The heterocyclic groups mentioned herein refer, unless otherwise noted,in particular to all of the possible positional isomers thereof.

Such as, for example, the term pyridyl or pyridinyl, alone or as part ofanother group, includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or1N—(R33)-piperidinyl includes 1N—(R33)-piperidin-2-yl,1N—(R33)-piperidin-3-yl and 1N—(R33)-piperidin-4-yl.

1N—(R33)-Piperidinyl stands for a piperidinyl radical which issubstituted by R33 at the nitrogen atom, such as, for example, anyradical, which is selected from the group consisting of piperidin-2-yl,piperidin-3-yl and piperidin-4-yl, and which is substituted by R33 atits nitrogen atom.

4N—(R322)-Piperazin-1-yl stands for a piperazin-1-yl radical which issubstituted at its nitrogen atom in the 4-position by R322.

4N-(1-4C-Alkyl)piperazin-1-yl stands for a piperazin-1-yl radical whichis substituted at its nitrogen atom in the 4-position by one of theabovementioned 1-4C-alkyl radicals, such as e.g.4N-methyl-piperazin-1-yl.

2-(R41)-Ethyl stands for an ethyl radical substituted in 2-position byR41.

In the meaning of the present invention, it is to be understood, that,when two structural portions of the compounds according to thisinvention are linked via a constituent which has the meaning “bond”,then said two portions are directly attached to another via a singlebond.

Constituents which are substituted as stated herein, may be substituted,unless otherwise noted, at any possible position.

The substituent R2 of compounds of formula I can be attached in theortho, meta or para position with respect to the binding position inwhich the phenyl ring is bonded to the amino group, whereby preferenceis given to the attachement in the meta or, particularly, para position.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Suitable salts for compounds according to this invention—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-insoluble and, particularly,water-soluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothis invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds according to thisinvention as well as their salts may contain, e.g. when isolated incrystalline form, varying amounts of solvents. Included within the scopeof the invention are therefore all solvates and in particular allhydrates of the compounds according to this invention as well as allsolvates and in particular all hydrates of the salts of the compoundsaccording to this invention.

Compounds according to this invention worthy to be mentioned are thosecompounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, di-(1-4C-alkoxy)-phenyl, or        R11-substituted phenyl, in which    -   R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,        1-4C-alkoxy, completely or predominantly fluorine-substituted        1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino, or        di-1-4C-alkylamino,

R2 is amino, carboxyl, 1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or—C(O)—N(R4)R5, in which

-   -   R3 is 1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl,        trifluoromethyl, phenyl, R31-substituted phenyl, furanyl,        imidazol-4-yl, pyridinyl, R32-substituted 1-4C-alkyl, or        1N—(R33)-piperidinyl, in which    -   R31 is 1-4C-alkoxy, morpholino, or di-1-4C-alkylamino,    -   R32 is hydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl,        R321-substituted phenyl, di-1-4C-alkylamino, morpholino, or        4N—(R322)-piperazin-1-yl, in which    -   R321 is 1-4C-alkoxy,    -   R322 is 1-4C-alkyl,    -   R33 is hydrogen, 1-4C-alkyl, or 1-4C-alkylcarbonyl,    -   R4 is hydrogen, 1-4C-alkyl, R41-substituted 2-4C-alkyl, phenyl,        R42-substituted phenyl, or pyridinyl, in which    -   R41 is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino,    -   R42 is 1-4C-alkoxy, or di-1-4C-alkylamino,    -   R5 is hydrogen, or 1-4C-alkyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl,    -   and the salts of these compounds.

Compounds according to this invention more worthy to be mentioned arethose compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, pyridinyl, thiophenyl, dimethoxyphenyl, or        R11-substituted phenyl, in which    -   R11 is methyl, tertbutyl, chlorine, fluorine, bromine,        trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy,        phenoxy, methoxycarbonyl, morpholino, or dimethylamino,    -   R2 is amino, carboxyl, 1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or        —C(O)—N(R4)R5, in which    -   R3 is 1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl,        trifluoromethyl, phenyl, R31-substituted phenyl, furanyl,        imidazol-4-yl, pyridinyl, R32-substituted 1-4C-alkyl, or        1N—(R33)-piperidinyl, in which    -   R31 is 1-4C-alkoxy, morpholino, or di-1-4C-alkylamino,    -   R32 is hydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl,        R321-substituted phenyl, di-1-4C-alkylamino, morpholino, or        4N—(R322)-piperazin-1-yl, in which    -   R321 is 1-4C-alkoxy,    -   R322 is 1-4C-alkyl,    -   R33 is hydrogen, 1-4C-alkyl, or 1-4C-alkylcarbonyl,    -   R4 is hydrogen, 1-4C-alkyl, R41-substituted 2-4C-alkyl, phenyl,        R42-substituted phenyl, or pyridinyl, in which    -   R41 is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino,    -   R42 is 1-4C-alkoxy, or di-1-4C-alkylamino,    -   R5 is hydrogen, or 1-4C-alkyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl,    -   and the salts of these compounds.

Compounds according to this invention in particular worthy to bementioned are those compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond, or methylene (—CH₂—),    -   A is phenyl, or R11-substituted phenyl, in which    -   R11 is methyl, chlorine, fluorine, bromine, trifluoromethyl,        hydroxyl, methoxy, phenoxy, methoxycarbonyl, or dimethylamino,    -   R2 is amino, carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or        —C(O)—N(R4)R5, in which    -   R3 is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl,        phenyl, R31-substituted phenyl, furanyl, imidazol-4-yl,        pyridinyl, R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl,        in which    -   R31 is methoxy, morpholino, or dimethylamino,    -   R32 is hydroxyl, benzyloxy, methoxy, phenyl, R321-substituted        phenyl, dimethylamino, morpholino, or 4N-methyl-piperazin-1-yl,        in which    -   R321 is methoxy,    -   R33 is hydrogen, methyl, or acetyl,    -   R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl, R42-substituted        phenyl, or pyridinyl, in which    -   R41 is hydroxyl, methoxy, dimethylamino, or morpholino,    -   R42 is methoxy, or dimethylamino,    -   R5 is hydrogen, or methyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, or 4N-methyl-piperazin-1-yl,    -   and the salts of these compounds.

Compounds according to this invention in more particular worthy to bementioned are those compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond,    -   A is phenyl, or R11-substituted phenyl, in which    -   R11 is fluorine, bromine, trifluoromethyl, or methoxy,    -   whereby in particular    -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 2-bromo-phenyl,        2-fluoro-phenyl, or 2-(trifluoromethyl)-phenyl;    -   R2 is attached in the meta or para position with respect to the        binding position in which the phenyl ring is bonded to the amino        group of the triazolophthalazine scaffold, and is amino,        carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in        which    -   R3 is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl,        phenyl, R31-substituted phenyl, furanyl, imidazol-4-yl,        pyridinyl, R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl,        in which    -   R31 is methoxy, morpholino, or dimethylamino,    -   R32 is hydroxyl, benzyloxy, methoxy, phenyl, R321-substituted        phenyl, dimethylamino, morpholino, or 4N-methyl-piperazin-1-yl,        in which    -   R321 is methoxy,    -   R33 is hydrogen, methyl, or acetyl,    -   R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl, R42-substituted        phenyl, or pyridinyl, in which    -   R41 is hydroxyl, methoxy, dimethylamino, or morpholino,    -   R42 is methoxy, or dimethylamino,    -   R5 is hydrogen, or methyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, or 4N-methyl-piperazin-1-yl,    -   and the salts of these compounds.

Emphasis is given to compounds of formula I, in which

-   -   R1 is —U-A, in which    -   U is a direct bond,    -   A is phenyl, or R11-substituted phenyl, in which    -   R11 is fluorine, bromine, chlorine, trifluoromethyl, methyl or        methoxy,

R2 is attached in the meta or para position with respect to the bindingposition in which the phenyl ring is bonded to the amino group of thetriazolophthalazine scaffold, and is amino, carboxyl, methoxycarbonyl,—N(H)—C(O)R3, or —C(O)—N(R4)R5, in which

-   -   R3 is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl,        phenyl, R31-substituted phenyl, furanyl, imidazol-4-yl,        pyridinyl, R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl,        in which    -   R31 is methoxy, morpholino, or dimethylamino,    -   R32 is hydroxyl, benzyloxy, methoxy, phenyl, R321-substituted        phenyl, dimethylamino, morpholino, or 4N-methyl-piperazin-1-yl,        in which    -   R321 is methoxy,    -   R33 is hydrogen, methyl, or acetyl,    -   R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl, R42-substituted        phenyl, or pyridinyl, in which    -   R41 is hydroxyl, methoxy, dimethylamino or morpholino,    -   R42 is methoxy, or dimethylamino,    -   R5 is hydrogen, or methyl,    -   or R4 and R5 together and with inclusion of the nitrogen atom,        to which they are bonded, form a heterocyclic ring radical Het,        in which    -   Het is morpholino, 4N-methyl-piperazin-1-yl, or        4N-ethyl-piperazin-1-yl    -   and the salts of these compounds.

A special interest in the compounds according to this invention refersto those compounds of formula I which are included—within the scope ofthis invention—by one or, when possible, by more of the followingspecial embodiments:

A special embodiment (embodiment 1) of the compounds according to thepresent invention refers to those compounds of formula I, in which

-   -   U is a direct bond, and    -   A is phenyl, or R11-substituted phenyl.

Another special embodiment (embodiment 2) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is a direct bond, and    -   A is pyridinyl or thiophenyl, such as e.g. pyridin-4-yl.

Another special embodiment (embodiment 3) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is methylene, and    -   A is phenyl, or R11-substituted phenyl.

Another special embodiment (embodiment 3-1) of the compounds accordingto the present invention refers to those compounds of formula I, inwhich

-   -   R1 is —U-A, in which    -   U is methylene (—CH₂—),    -   A is phenyl, or R11-substituted phenyl;

Another special embodiment (embodiment 3-1-1) of the compounds accordingto the present invention refers to those compounds of formula I, inwhich

-   -   R1 is (4-methoxy-phenyl)-methyl;    -   and the salts of these compounds.

Another special embodiment (embodiment 4) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   U is methylene, and    -   A is pyridinyl or thiophenyl, such as e.g. thiophen-2-yl.

Another special embodiment (embodiment 5) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is —N(H)—C(O)R3.

Another special embodiment (embodiment 6) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is —C(O)—N(R4)R5.

Another special embodiment (embodiment 7) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is (4-methoxy-phenyl)-methyl, or 4-methoxy-phenyl.

Another special embodiment (embodiment 8) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl.

Another special embodiment (embodiment 9) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is (4-methoxy-phenyl)-methyl, 2-hydroxy-phenyl, phenyl,        3-methoxycarbonyl-phenyl, or 4-methoxy-phenyl, 2-methoxy-phenyl,        2-bromo-phenyl, 2-fluoro-phenyl, or 2-(trifluoromethyl)-phenyl,        or 2-chloro-phenyl, 4-bromo-phenyl, 2-methyl-phenyl.

Another special embodiment (embodiment 10) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl, 2-methoxy-phenyl, 2-bromo-phenyl,        2-fluoro-phenyl, or 2-(trifluoromethyl)-phenyl.

Another special embodiment (embodiment 11) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R1 is 2-bromo-phenyl.

Another special embodiment (embodiment 12) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is —N(H)—C(O)R3, in which    -   R3 is 1N—H-piperidinyl, especially 1N—H-piperidin-2-yl or        1N—H-piperidin-3-yl.

Another special embodiment (embodiment 13) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is attached in the meta position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold.

Another special embodiment (embodiment 14) of the compounds according tothe present invention refers to those compounds of formula I, in which

-   -   R2 is attached in the para position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold.

Another special embodiment (embodiment 15) of the compounds according tothe present invention refers to those compounds of formula I comprisingone or more of the following:

-   -   R1 is 4-methoxy-phenyl;    -   R2 is attached in the para position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold; and    -   R2 is —N(H)—C(O)R3, in which    -   R3 is 1N—H-piperidinyl;    -   and the salts of these compounds.

A special group of the compounds according to the present inventionrefers to those compounds of formula I, in which

-   -   R1 is 4-methoxy-phenyl, or 2-bromo-phenyl,    -   R2 is attached in the para position with respect to the binding        position in which the phenyl ring is bonded to the amino group        of the triazolophthalazine scaffold, and is —N(H)—C(O)R3, in        which    -   R3 is 1N—H-piperidinyl, especially 1N—H-piperidin-2-yl or        1N—H-piperidin-3-yl.

The compounds according to the invention can be prepared e.g. asdescribed exemplarily as follows and according to the followingspecified reaction steps, or, particularly, in a manner as described byway of example in the following examples, or analogously or similarlythereto according to preparation procedures or synthesis strategiesknown to the person skilled in the art.

As shown in reaction scheme 1 below, compounds of formula I, in which R1and R2 have those of the abovementioned meanings which are suitable forthe conditions of the nucleophilic substitution reaction in which theyare built, can be obtained from corresponding compounds of formula II,in which X is a suitable leaving group, particularly chlorine, byreaction with corresponding aniline derivatives of formula III.

Said nucleophilic substitution reaction can be carried out as describedin the following examples or as known to the skilled person; thus,depending on the reactivity of the reactants, it can be carried out bymelting the reaction partners without solvent together or by reactingthe reaction partners in a suitable solvent, such as e.g.N,N-dimethylformamide, in the presence of a suitable base, such as e.g.sodium hydride or potassium carbonate, at a temperature to allow thereaction to procede (this may be e.g., depending on the reactants,ambient temperature, elevated temperature, or reflux temperature of thesolvent used or, under appropriate conditions, beyond it), optionallyunder microwave irradiation.

Compounds of formula III are known or can be obtained in a known manner.

Compounds of formula II can be obtained as described later herein.

Isoamides of formula Ia′ as shown below, in which R1 and R3 have theabovementioned meanings, especially those, which are not accessible bythe synthesis strategy shown in reaction scheme 1 above, can be obtainedas shown in reaction scheme 2 below by acylation of compounds of formulaIa, in which R1 has the meanings given above, with compounds of formulaR3-C(O)Y, in which Y is a suitable leaving group, such as e.g. chlorine,under conditions habitual per se to the skilled person.

Alternatively, compounds of the formula Ia′ can also be prepared fromthe corresponding compounds of formula la and corresponding compounds offormula R3-C(O)Y, in which Y is hydroxyl, by reaction with amide bondlinking reagents known to the person skilled in the art under conditionscustomary to the skilled person. Exemplary amide bond linking reagentsknown to the person skilled in the art which may be mentioned are, forexample, the carbodiimides (e.g. dicyclohexylcarbodiimide or,preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride), azodicarboxylic acid derivatives (e.g. diethylazodicarboxylate), uronium salts [e.g.O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate orO-(benzotriazol-1yl)-N,N,N′,N′-tetramthyl-uronium-hexafluorophosphate]and N,N′-carbonyldiimidazole. In the scope of this invention1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC orEDCI) is particularly to be mentioned.

Compounds of formula R3-C(O)Y are known or can be obtained in a knownmanner.

Compounds of formula Ia can be obtained directly as shown in reactionscheme 1 and described above by using diaminobenzene; or they areaccessible by reduction of the nitro group of compounds of formula I, inwhich R1 has the meanings mentioned above and R2 is nitro, with the aidof an appropriate reducing agent, such as e.g. tin dichloride.

Compounds of formula I, in which R1 has the meanings mentioned above andR2 is nitro, can be obtained according to reaction scheme 1.

Amides of formula Ib′ as shown below, in which R1, R4 and R5 have theabovementioned meanings, especially those, which are not accessible bythe synthesis strategy shown in reaction scheme 1 above, can be obtainedas shown in reaction scheme 3 below by amidification of benzoic acids offormula Ib, in which R1 has the meanings given above, with correspondingamines of formula HN(R4)R5 under conditions customary per se to theskilled person.

This amidification reaction can be carried out in the presence ofsuitable amide bond linking reagents, such as e.g. those mentionedabove, particularly 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC or EDCI).

Compounds of formula HN(R4)R5 are known or can be obtained in a knownmanner.

Benzoic acids of formula Ib, in which R1 has the meanings given above,can be prepared by saponification of corresponding ester compounds offormula I, in which R2 is 1-4C-alkoxycarbonyl, particularlymethoxycarbonyl.

Compounds of formula I, in which R1 has the meanings mentioned above andR2 is 1-4C-alkoxycarbonyl, particularly methoxycarbonyl, can be obtainedaccording to reaction scheme 1.

Starting compounds of formula II can be obtained as shown in reactionscheme 4 or as specified in the following examples; or they areart-known, such as e.g. from R. W. Carling et al., J. Med. Chem. Vol.47, No. 7, 1807-1822 (2004), or they can be prepared according to knownprocedures or analogously or similarly to art-described compounds.

Compounds of formula II, in which R1 has the meanings mentioned aboveand X is a suitable leaving group, particularly chlorine, can beobtained from corresponding compounds of formula IV either in one stepby cyclization reaction with corresponding compounds of formulaR1-C(O)Z, in which Z is a suitable leaving group, such as e.g. chlorine;or in two steps via the isolatable intermediate of formula III, which isaccessible by acylation of compounds of formula IV and which can befurther reacted to desired compounds of formula II by condensationreaction.

Said reactions can be carried out as described in the followingexamples, or under conditions known to the skilled person or analogouslyto art-known reactions similar thereto. Thus, the aforementionedone-step cyclization reaction can be carried out similarly as describedin J. Med. Chem. Vol. 31, 1988, p. 1115, in a suitable solvent, such ase.g. toluene, pyridine or dioxane, in the presence of a suitable base(e.g. triethylamine) at elevated temperature or the reflux temperatureof the solvent used.

Compounds of formula IV can be obtained by nucleophilic substitution ofcompounds of formula V, in which X and X′ can be the same and aresuitable leaving groups, particularly X and X′ are both chlorine, andhydrazine.

Compounds of formulae R1-C(O)Z and V are known or can be obtained in aknown manner.

It is to be understood for the skilled worker, that certain compounds offormula I according to this invention can be converted into furthercompounds of formula I by art-known synthesis strategies and reactionshabitual per se to a person of ordinary skill in the art, like e.g. asdescribed above.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The substances of formula I according to the invention are isolated andpurified in a manner known per se, for example by distilling off thesolvent under reduced pressure and recrystallizing the residue obtainedfrom a suitable solvent or subjecting it to one of the customarypurification methods, such as, for example, column chromatography on asuitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow-molecular-weight aliphatic alcohol, such as ethanol or isopropanol)which contains the desired acid or base, or to which the desired acid orbase is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted into thefree compounds, which can in turn be converted into salts, byalkalization or by acidification. In this manner, pharmacologicallyunacceptable salts can be converted into pharmacologically acceptablesalts.

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds of formula I. All these otherpossible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicite, implicite or inherent disclosure) of the presentinvention without departing from the spirit and scope of this inventionas defined by the appended claims.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds of formula I, whosepreparation is not explicitly described, can be prepared in an analogousor similar manner or in a manner familiar per se to the person skilledin the art using customary process techniques.

The compounds of formula I according to the present invention which arementioned in the following examples, particularly which are mentioned asfinal compounds, as well as their salts are a preferred subject of thepresent invention.

In the examples, MS stands for mass spectrum, calc. for calculated, fnd.for found, and other abbreviations have their meanings customary per seto the skilled person.

Examples

Final Compounds:

1.N-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]benzene-1,4-diamine

1.0 g 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and 2.7 g p-phenylene-diamine are stirred at 170° C. for 5h. The reaction mixture is diluted with 6 ml ethanol and the precipitateis filtered with suction. The solid is recrystallized fromN,N-dimethylformamide to yield 1.04 g of the title compound (m.p.: 295°C.).

EF: C₂₂ H₁₈ N₆ O (382.43) found: [M+1] 383.3

Alternative reaction procedure I:

100 mg 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1), 1-3 mmol of the appropriate aniline derivative and 30 mgpotassium carbonate are stirred in 2,5 ml N,N-dimethylformamide at 140°C. for 4 h or at 200° C. for 10 min under microwave irradiation. Thereaction mixture is diluted with dichloromethane/water or sodiumhydroxide solution, the precipitate is filtered with suction, washedwith water and recrystallized from N,N-dimethylformamide.

Alternative reaction procedure II:

2.5 mmol of the appropriate aniline derivative and 2.5 mmol sodiumhydride (60%) in 2.5 ml N,N-dimethylformamide are treated with 100 mg6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) at ambient temperature. After 10 min the reaction mixtureis added to water, the precipitate is filtered with suction and thesolid is recrystallized from N,N-dimethylformamide.

Alternative work up procedure:

The product is purified by column chromatography via silica gel.

2.N-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]benzene-1,3-diamine

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and m-phenylene-diamine, the title compound can beobtained analogously to one of the procedures as described for compound1.

m.p.: 295° C.

EF: C₂₂ H₁₈ N₆ O (382.43) found: [M+1] 383.3

Starting fromN-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine(compound 1) and the appropriate carboxylic acid derivatives thefollowing compounds 3 to 26 can be obtained analogously as described forcompound 22.

3.C-Dimethylamino-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C26 H25 N7 O2 MS: calc. C26 H25 N7 O2 (467.53) found [M+1] 467.9

4.2-Methoxy-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C25 H22 N6 O3 MS: calc. C25 H22 N6 O3 (454.49) found [M+1] 454.8

5.3-Methoxy-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-propionamide

C26 H24 N6 O3 MS: calc. C26 H24 N6 O3 (468.52) found [M+1] 469.0

6.3-Methoxy-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

7.Dimethylamino-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 529.7

8.Dimethylamino-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 530.0

9.N-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-isonicotinamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.8

10.N-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-nicotinamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.9

11. 1H-Imidazole-4-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H20 N8 O2 MS: calc. C26 H20 N8 O2 (476.50) found [M+1] 476.7

12. Piperidine-2-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

13. Piperidine-3-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

14. 1-Acetyl-piperidine-4-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C30 H29 N7 O3 MS: calc. C30 H29 N7 O3 (535.61) found [M+1] 535.9

15.N-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-2-phenyl-acetamide

C30 H24 N6 O2 MS: calc. C30 H24 N6 O2 (500.56) found [M+1] 500.9

16.2-(4-Methoxy-phenyl)-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C31 H26 N6 O3 MS: calc. C31 H26 N6 O3 (530.59) found [M+1] 531.0

17.2,2,2-Trifluoro-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C24 H17 F3 N6 O2 MS: calc. C24 H17 F3 N6 O2 (478.44) found [M+1] 478.8

18. Cyclopropanecarboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H22 N6 O2 MS: calc. C26 H22 N6 O2 (450.50) found [M+1] 450.8

19. Cyclohexanecarboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C29 H28 N6 O2 MS: calc. C29 H28 N6 O2 (492.59) found [M+1] 492.8

20.2-Benzyloxy-N-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C31 H26 N6 O3 MS: calc. C31 H26 N6 O3 (530.59) found [M+1] 530.9

21. Furan-3-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H20 N6 O3 MS: calc. C27 H20 N6 O3 (476.50) found [M+1] 476.8

22. Pyridine-2-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

To a solution of picolinic acid (0.27 mmol) and 1-hydroxybenzotriazolehydrate (0.27 mmol) in DMF (5 mL) is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.27 mmol)followed byN-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine(compound 1) (0.26 mmol). The reaction mixture is stirred at roomtemperature overnight and concentrated in vacuum. Water (10 mL) is addedto the residue and the resulting precipitate is filtered and washed withethyl acetate and diethylether. The solid is dried azeotropically withtoluene to yield 103 mg of the title compound as light brown solid.

m.p.: 301° C.-305° C.

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.9

23. Piperidine-4-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 494.2

24. Piperidine-4-carboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amidehydrochloride

C28 H28 Cl N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

25.N-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-2-morpholin-4-yl-acetamide

C28 H27 N7 O3 MS: calc. C28 H27 N7 O3 (509.57) found [M+1] 509.9

26.N-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-2-(4-methyl-piperazin-1-yl)-acetamide

C29 H30 N8 O2 MS: calc. C29 H30 N8 O2 (522.61) found [M+1] 522.8

Starting from the appropriate amino compounds selected from compounds 67to 70 and the appropriate carboxylic acid derivatives the followingcompounds 27 to 31 can be obtained analogously as described for compound22.

27. Piperidine-2-carboxylic acid{4-[3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H24 F3 N7 O MS: calc. C28 H24 F3 N7 O (531.54) found [M+1] 532.1

28. Piperidine-3-carboxylic acid{4-[3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H24 Br N7 O MS: calc. C27 H24 Br N7 O (542.44) found [M+1] 542.2

29. Piperidine-3-carboxylic acid{4-[3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H24 F3 N7 O MS: calc. C28 H24 F3 N7 O (531.54) found [M+1] 532.6

30. Piperidine-2-carboxylic acid{4-[3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H24 Br N7 O MS: calc. C27 H24 Br N7 O (542.44) found [M+1] 544.1

31. Piperidine-2-carboxylic acid{4-[3-(2-methoxy-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 494.1

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and the appropriate aniline derivatives, the followingcompounds 32 to 34 can be obtained analogously to one of the proceduresas described for compound 1.

32.N-{4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C24 H20 N6 O2 (424.47) found: [M+1] 425.3

33.N-{4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C29 H22 N6 O2 (486,54) m.p.: 323° C.

34. Furan-2-carboxylic acid{4-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H20 N6 O3 (476,5) m.p.: 303° C.

Starting fromN-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine(compound 2) and the appropriate carboxylic acid derivatives thefollowing compounds 35 to 63 can be obtained analogously as describedfor compound 22.

35. Cyclohexanecarboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C29 H28 N6 O2 MS: calc. C29 H28 N6 O2 (492.59) found [M+1] 492.9

36.N-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C29 H22 N6 O2 MS: calc. C29 H22 N6 O2 (486.54) found [M+1] 486.9

37.2-Benzyloxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C31 H26 N6 O3 MS: calc. C31 H26 N6 O3 (530.59) found [M+1] 530.9

38. Cyclopropanecarboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H22 N6 O2 MS: calc. C26 H22 N6 O2 (450.50) found [M+1] 451.0

39.2,2,2-Trifluoro-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C24 H17 F3 N6 O2 MS: calc. C24 H17 F3 N6 O2 (478.44) found [M+1] 478.7

40. Furan-2-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H20 N6 O3 MS: calc. C27 H20 N6 O3 (476.50) found [M+1] 476.8

41. Furan-3-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C27 H2O N6 O3 MS: calc. C27 H20 N6 O3 (476.50) found [M+1] 476.9

42. 1 H-Imidazole-4-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H20 N8 O2 MS: calc. C26 H20 N8 O2 (476.50) found [M+1] 476.8

43.C-Dimethylamino-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 529.9

44.N-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-isonicotinamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.8

45.2-Methoxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C25 H22 N6 O3 MS: calc. C25 H22 N6 O3 (454.49) found [M+1] 454.8

46.4-Methoxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

47.3-Methoxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.8

48.2-(4-Methoxy-phenyl)-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C31 H26 N6 O3 MS: calc. C31 H26 N6 O3 (530.59) found [M+1] 531.0

49.N-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-2-phenyl-acetamide

C30 H24 N6 O2 MS: calc. C30 H24 N6 O2 (500.56) found [M+1] 500.9

50.N-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-nicotinamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.7

51.Dimethylamino-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 529.9

52.C-Dimethylamino-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C26 H25 N7 O2 MS: calc. C26 H25 N7 O2 (467.53) found [M+1] 467.9

53.3-Methoxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]phenyl}-propionamide

C26 H24 N6 O3 MS: calc. C26 H24 N6 O3 (468.52) found [M+1] 469.0

54. 1-Acetyl-piperidine-4-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C30 H29 N7 O3 MS: calc. C30 H29 N7 O3 (535.61) found [M+1] 535.9

55. Pyridine-2-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.8

56.Dimethylamino-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 529.9

57. Piperidine-4-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

58. Piperidine-3-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

59. Piperidine-2-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.8

60.2-Hydroxy-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C24 H20 N6 O3 MS: calc. C24 H20 N6 O3 (440.47) found [M+1] 440.9

61.N-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acrylamide

C25 H20 N6 O2 MS: calc. C25 H20 N6 O2 (436.48) found [M+1] 436.8

62. 1-Methyl-piperidine-4-carboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]phenyl}-amide

C29 H29 N7 O2 MS: calc. C29 H29 N7 O2 (507.60) found [M+1] 507.9

63.Dimethylamino-N-{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-butyramide

C28 H29 N7 O2 MS: calc. C28 H29 N7 O2 (495.59) found [M+1] 495.9

Starting from the appropriate amino compounds selected from compounds 71to 74 and the appropriate carboxylic acid derivatives the followingcompounds 64 to 65 can be obtained analogously as described for compound22.

64. Cyclopropanecarboxylic acid{3-[3-(2-fluoro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C25 H19 F N6 O MS: calc. C25 H19 F N6 O (438.47) found [M+1] 439.1

65. Cyclopropanecarboxylic acid{3-[3-(2-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H22 N6 O2 MS: calc. C26 H22 N6 O2 (450.50) found [M+1] 451.1

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and the appropriate aniline derivative, the followingcompound 66 can be obtained analogously to one of the procedures asdescribed for compound 1.

66.N-{3-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-acetamide

C24 H20 N6 O2 424.47 m.p.: 295° C.

Starting from the appropriate starting compound selected from A2 to A9the following compounds 67 to 74 can be obtained by reduction reactionanalogously as described for compound 74a; or, alternatively, thefollowing compounds 67 to 74a can be obtained analogously as describedfor compound 1.

67.N-[3-(2-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine

C22 H18 N6 O MS: calc. C22 H18 N6 O (382.43) found [M+1] 383.1

68.N-[3-(2-Fluorophenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine69.N-[3-(2-Bromophenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine

C21 H15 Br N6 MS: calc. C21 H15 Br N6 (431.30) found [M+1] 431.0

70.N-[3-(2-Trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine

C22 H15 F3 N6 MS: calc. C22 H15 F3 N6 (420.40) found [M+1] 421.0

71.N-[3-(2-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine

C22 H18 N6 O MS: calc. C22 H18 N6 O (382.43) found [M+1] 383.1

72.N-[3-(2-Fluorophenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine73.N-[3-(2-Bromophenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine

C21 H15 Br N6 MS: calc. C21 H15 Br N6 (431.30) found [M+1] 433.1

74.N-[3-(2-Trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine74a.N-[3-(2-Methyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine

To a suspension of(3-nitro-phenyl)-(3-o-tolyl-[1,2,4]triazolo[3,4-a]-phthalazin-6-yl)-amine(compound A10) (263 mg, 0.66 mmol) in a 2:1 mixture of glacial aceticacid and 37% hydrochloric acid (18 ml) is added tin chloride dihydrate(450 mg, 1.99 mmol). The mixture is stirred at 90° C. for 2 days. Uponcooling, the precipitate is filtered and the filtrate concentrated.Purification of residue by column chromatography (CH₂Cl₂/MeOH, 95:5)gives 205 mg of an off-white solid which is triturated with a 1:1mixture of isopropanol and petroleum ether to yield 77 mg of the titlecompound as off-white needles.

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and the appropriate aniline derivatives, the followingcompounds 75 and 76 can be obtained analogously to one of the proceduresas described for compound 1.

75.4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid methyl ester

C24 H19 N5 O3 425.45 found: [M+1] 426.4

76.3-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid methyl ester

C24 H19 N5 O3 425.45 found: [M+1] 426.3

77.4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid

40 mg4-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid methyl ester (compound 75), 25 mg potassium hydroxide and 150 μlwater are stirred in 2 ml methanol at 100° C. for 1 h. The reactionmixture is filtered with suction, the filtrate is diluted with 10 mlwater and acidified to pH2-3 with 2M hydrochloric acid. The precipitateis filtered with suction, washed with water and dried to yield 23 mg ofthe title compound.

EF: C₂₃ H₁₇ N₅ O₃ (411.42) found: [M+1] 412.3

Alternative Reaction Procedure:

In a sealed tube, to a solution of sodium methoxide in methanol,prepared by addition of sodium (590 mg, 25.4 mmol) in anhydrous methanol(20 ml) under argon, are added4-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid methyl ester (compound 75) (4.0 g, 9.40 mmol and diisopropylamine(32 ml). The mixture is stirred at 100° C. for 3 days and evaporated.The residue is washed with ethyl acetate and a minimum of methanol toyield 3.78 g of the title compound as light yellow powder.

m.p.: 309° C. (decomp.)

78.3-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid

Starting from3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid methyl ester (compound 76) the title compound can be obtainedanalogously as described for compound 77.

EF: C₂₃ H₁₇ N₅ O₃ (411.42) found: [M+1] 411.8

Starting from4-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid (compound 77) and the appropriate amine derivatives, the followingcompounds 79 to 89 can be obtained analogously as described for compound103.

79.4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide

C29 H29 N7 O3 MS: calc. C29 H29 N7 O3 (523.60) found [M+1] 524.0

80.N-(3-Methoxy-phenyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.8

81.N-(4-Methoxy-phenyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

82.4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-phenyl-benzamide

C29 H22 N6 O2 MS: calc. C29 H22 N6 O2 (486.54) found [M+1] 486.9

83.N-(4-Dimethylamino-phenyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 529.8

84.N-(2-Methoxy-phenyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

85.4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-methyl-benzamide

C24 H20 N6 O2 MS: calc. C24 H20 N6 O2 (424.47) found [M+1] 424.9

86.N-(2-Dimethylamino-ethyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C27 H27 N7 O2 MS: calc. C27 H27 N7 O2 (481.56) found [M+1] 481.7

87.N-(2-Methoxy-ethyl)-4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C26 H24 N6 O3 MS: calc. C26 H24 N6 O3 (468.52) found [M+1] 468.7

88.1-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-methanone

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 494.0

89.4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N,N-dimethyl-benzamide

C25 H22 N6 O2 MS: calc. C25 H22 N6 O2 (438.49) found [M+1] 439.0

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and the appropriate aniline derivatives, the followingcompounds 91 and 92 can be obtained analogously to one of the proceduresas described for compound 1.

91.4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C23 H18 N6 O2 410.44 found: [M+1] 411.3

92.1-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-morpholin-4-ylmethanone

C27 H24 N6 O3 480.53 m.p.: 295° C.

Starting from3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid (compound 78) and the appropriate amine derivatives, the followingcompounds 90 and 93 to 108 can be obtained analogously as described forcompound 103.

90.N-(2-Dimethylamino-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamidehydrochloride

C27 H28 Cl N7 O2 MS: calc. C27 H27 N7 O2 (481.56) found [M+1] 481.8

93.1-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-methanone

C28 H27 N7 O2 MS: calc. C28 H27 N7 O2 (493.57) found [M+1] 493.9

94.1-{3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-morpholin-4-yl-methanone

C27 H24 N6 O3 MS: calc. C27 H24 N6 O3 (480.53) found [M+1] 480.9

95.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide

C29 H29 N7 O3 MS: calc. C29 H29 N7 O3 (523.60) found [M+1] 523.8

96.N-(2-Dimethylamino-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C27 H27 N7 O2 MS: calc. C27 H27 N7 O2 (481.56) found [M+1] 481.9

97.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-pyridin-3-yl-benzamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.8

98.N-(2-Hydroxy-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C25 H22 N6 O3 MS: calc. C25 H22 N6 O3 (454.49) found [M+1] 454.8

99.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-pyridin-4-yl-benzamide

C28 H21 N7 O2 MS: calc. C28 H21 N7 O2 (487.53) found [M+1] 487.8

100.N-(4-Methoxy-phenyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

101.N-(3-Methoxy-phenyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

102.N-(2-Methoxy-phenyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 516.9

103.N-(4-Dimethylamino-phenyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

To a solution of3-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid (compound 78) (100 mg, 0.24 mmol) and 1-hydroxybenzotriazolehydrate (35 mg, 0.26 mmol) in DMF (5 mL) is added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.26mmol) followed by N,N-dimethyl-phenylene diamine (35 mg, 0.26 mmol). Thereaction mixture is stirred at room temperature for 2 days andconcentrated in vacuum. Water (20 mL) is added to the residue and theresulting precipitate is filtered and washed with methanol anddichloromethane. The solid is dried azeotropically with toluene to yield79 mg of the title compound as grey powder.

m.p.: 314° C.-318° C.

C31 H27 N7 O2 MS: calc. C31 H27 N7 O2 (529.61) found [M+1] 530.0

104.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-phenyl-benzamide

C29 H22 N6 O2 MS: calc. C29 H22 N6 O2 (486.54) found [M+1] 486.8

105.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N,N-dimethyl-benzamide

C25 H22 N6 O2 MS: calc. C25 H22 N6 O2 (438.49) found [M+1] 438.8

106.N-(2-Methoxy-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C26 H24 N6 O3 MS: calc. C26 H24 N6 O3 (468.52) found [M+1] 468.8

107.3-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamidehydrochloride

C29 H30 Cl N7 O3 MS: calc. C29 H29 N7 O3 (523.60) found [M+1] 523.8

108.N-(2-Dimethylamino-ethyl)-3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamidehydrochloride

C27 H28 Cl N7 O2 MS: calc. C27 H27 N7 O2 (481.56) found [M+1] 481.8

Starting from6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine(compound A1) and the appropriate aniline derivatives, the followingcompounds 109 and 110 can be obtained analogously to one of theprocedures as described for compound 1.

109.3-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzamide

C23 H18 N6 O2 410.44 m.p.: 296° C.

110.3-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-N-methylbenzamide

C24 H20 N6 O2 424.47 m.p.: 316° C.

111.N-{4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-4-morpholin-4-yl-benzamide

100 mgN-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine(compound 1), 10 mg dimethylaminopyridine and 145 mg4-morpholin-4-yl-benzoyl chloride are stirred in 12 ml toluene for 1-3 hat boiling temperature. After cooling to ambient temperature, theprecipitate is filtered with suction and the solid is recrystallizedfrom N,N-dimethylformamide to yield 15 mg of the title compound (m.p.:313° C.).

EF: C₃₃ H₂₉ N₇ O₃ (571.64) found: [M+1] 572.4

Starting fromN-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,4-diamine(compound 1) and the appropriate carboxylic acid derivative thefollowing compound 112 can be obtained analogously as compounds 3-26, asdescribed for compound 22.

112.4-Methoxy-N-{4-[3-(4-methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-benzamide

C30 H24 N6 O3 MS: calc. C30 H24 N6 O3 (516.56) found [M+1] 517.3

Starting from the appropriate starting nitro compounds A11 (for 113) orA12 (for 114), the following compounds 113 and 114 can be obtained byreduction reaction analogously as described for compound 74a; or,alternatively, starting from B8 (for 113) or B9 (for 114) the followingcompounds 113 and 114 can be obtained analogously as described forcompound 1.

113.N-[3-(4-Bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine

C21 H15 Br N6 MS: calc. C21 H15 Br N6 (431.30) found [M+1] 431.1

114.N-[3-(2-Chloro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine

C21 H15 Cl N6 MS: calc. C21 H15 Cl N6 (386.85) found [M+H] 387.0

Starting fromN-[3-(4-Bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl]-benzene-1,3-diamine(compound 113) and the appropriate carboxylic acid derivative thefollowing compound 115 can be obtained analogously as compounds 3-26, asdescribed for compound 22.

115. Cyclopropanecarboxylic acid{3-[3-(4-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C25 H19 Br N6 O MS: calc. C25 H19 Br N6 O (499.37) found [M+H] 499.0

Starting from compound 74a (for 116) or compound 74 (for 117) and theappropriate carboxylic acid derivatives, the following compounds N6 andN7 can be obtained analogously as compounds 64/65, as described forcompound 22.

116. Cyclopropanecarboxylic acid[3-(3-o-tolyl-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino)-phenyl]-amide

C26 H22 N6 O MS: calculated C26 H22 N6 O (434.5) found (M+1) 435.2

117. Cyclopropanecarboxylic acid{3-[3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide

C26 H19 F3 N6 O MS: calculated C26 H19 F3 N6 O (488.48) found (M+1)489.1

Starting from4-[3-(4-Methoxyphenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-benzoicacid (compound 77) and the appropriate amine derivative, the followingcompounds 118 can be obtained analogously as compounds 79-89, asdescribed for compound 103.

118.1-(4-Ethyl-piperazin-1-yl)-1-{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-methanone

C29 H29 N7 O2 MS: C29 H29 N7 O2 calculated 507.60 found (M+H) 508.1

Starting Compounds

A1. 6-Chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

6.0 g (4-chloro-phthalazin-1-yl)-hydrazine (compound B1) are suspendedin a mixture of 160 ml toluene and 18 ml triethylamine at 60° C. andtreated with a solution of 6.0 g 4-methoxy-benzoyl chloride in 48 mltoluene. The mixture is stirred at 110° C. for 6 h, cooled to ambienttemperature, filtered with suction and rinsed with toluene. The solid isrecrystallized from N,N-dimethylformamide, the precipitate is washedwith water and dried to yield 5.2 g of the title compound (m.p.:192-193° C.).

EF: C₁₆ H₁₁ Cl N₄ O (310.75) found: [M+1] 311.2

Alternative Work Up Procedure:

The products can be purified by column chromatography via silica gel.

Starting from the appropriate starting compound B2 to B9 and theappropriate aniline derivative, the following compounds A2 to A12 may beobtained analogously to one of the procedures as described for compound1.

A2.(3-Nitro-phenyl)-{3-(2-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA3.(3-Nitro-phenyl)-{3-(2-fluoro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA4.(3-Nitro-phenyl)-{3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA5.(3-Nitro-phenyl)-{3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA6.(4-Nitro-phenyl)-{3-(2-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA7.(4-Nitro-phenyl)-{3-(2-fluoro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA8.(4-Nitro-phenyl)-{3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA9.(4-Nitro-phenyl)-{3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-yl}-amineA10.(3-Nitro-phenyl)-(3-o-tolyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-amineA11.(3-Nitro-phenyl)-(3-(4-bromo-phenyl)-[[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-amineA12.(3-Nitro-phenyl)-(3-(2-chloro-phenyl)-[[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-amineB1. (4-Chloro-phthalazin-1-yl)-hydrazine

10 g commercially available dichlorophthalazine are added portionwise at90° C. to a solution of 50 ml ethanol and 20 ml hydrazine hydrate. After10 min the reaction mixture is cooled to ambient temperature, theprecipitate is filtered with suction and rinsed with ethanol to yield8.4 g of the title compound.

EF: C₈ H₇ Cl N₄ (194.62) found: [M+1] 195.0

Starting from (4-chloro-phthalazin-1-yl)-hydrazine (compound B1) and theappropriate benzoic acid derivatives, the following compounds B2 to B9can be obtained analogously to the procedure as described for compoundA1 or B7.

B2. 6-Chloro-3-(2-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine B3.6-Chloro-3-(2-fluoro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine B4.6-Chloro-3-(2-bromo-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine B5.6-Chloro-3-(2-trifluoromethyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazineB6. 6-Chloro-3-(2-methyl-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine B7.6-Chloro-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine

Step 1:

2.5 g (4-chloro-phthalazin-1-yl)-hydrazine (compound B1) are suspendedin 250 ml toluene and treated with a solution of 1.7 ml benzoic acidchloride in 50 ml toluene at reflux temperature. After 2 h the reactionmixture is cooled to ambient temperature and filtered with suction. Thefiltrate is concentrated under reduced pressure and the residue isrecrystallized from N,N-dimethylformamide to yield 1.2 g of benzoic acid(4-chloro-2H-phthalazin-1-ylidene)-hydrazide.

EF: C₁₅ H₁₁ Cl N₄ O (298.73) found: [M+1] 299.1

Step 2:

2.5 g benzoic acid (4-chloro-2H-phthalazin-1-ylidene)-hydrazide and 1 gtriethylamine hydrochloride are suspended in 60 ml ethylene glycol andstirred at 130° C. for 3 h. The reaction mixture is cooled to ambienttemperature and added to 600 ml water. The product is extracted withdichloromethane, the organic layer is dried with sodium sulphate andconcentrated under reduced pressure. The residue is recrystallized fromN,N-dimethylformamide to give the title compound.

EF: C15 H9 Cl N4 (280.72) found: [M+1] 281.2

Alternative Work Up Procedure:

The products can be purified by column chromatography via silica gel.

B8. 3-(4-Bromo-phenyl)-6-chloro-[1,2,4]triazolo[3,4-a]phthalazine

C15 H8 Br Cl N4 MS: calc. C15 H8 Br Cl N4 (359.61) found [M+1] 358.8

B9. 6-Chloro-3-(2-chloro-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine

C15 H8 Cl2 N4 MS: calc. C15 H8 Cl2 N4 (315.16) found [M+H] 314.8

Commercial Applicability

The compounds according to the invention have useful pharmacologicalproperties which make them industrially utilizable. As selectiveinhibitors of cyclic GMP-hydrolysing phosphodiesterases (cGMP-PDEinhibitors)—prefentially of type 2—, they are suitable on the one handas therapeutics for conditions of pathologically enhanced endothelialactivity and impaired endothelial barrier function such as septic shock,vascular edema, or diseases associated with unwanted neoangiogenesis. Onthe other hand, given the expression of PDE2 in neuronal tissue thecompounds may also be useful in neurodegenerative conditions. Inaddition, PDE2 is expressed in human platelets and PDE2 inhibitors wereshown to suppress platelet functions. In consequence, the compounds maybe used as anti-thrombotics/platelet aggregation inhibitors.Furthermore, since PDE2 was shown in myocardium the compounds may afforda potential to protect against arrhythmias.

On account of their cGMP-PDE (preferentially PDE2) inhibitingproperties, the compounds according to the invention can be employed inhuman and veterinary medicine as therapeutics, where they can be used,for example, for the treatment and prophylaxis of the followingillnesses: (1) all conditions of pathologically enhanced endothelialactivity/impaired endothelial barrier function such as multi-organfailure in particular acute respiratory distress syndrome (ARDS) inseptic shock, pneumonia, acute and chronic airway disorders of varyingorigin (rhinitis, bronchitis, bronchial asthma, emphysema, COPD),angioedema, peripheral edema, cerebral edema for example traumatic orfollowing stroke; (2) all conditions associated with pathologicallyenhanced neoangiogenesis such as all kinds of tumors (benign ormalignant) which are associated with neoangiogenesis and all kinds ofinflammatory diseases associated with neoangiogenesis for exampledisorders of the arthritis type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic conditions), all formsof psoriasis, retinal blindness, bronchial asthma, inflammatory boweldisease, transplant rejection, allograft rejections, atherosclerosis;(3) all conditions for which platelet aggregation inhibition inconjunction with reduction of enhanced endothelial activation isdesireable such as thrombembolic disorders and ischaemias coveringmyocardial infarct, cerebral infarct, transitory ischaemic attacks,angina pectoris, peripheral circulatory disorders, prevention ofrestenosis after thrombolysis therapy, percutaneous translumialangioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA)and bypass; (4) all types of impaired cognition in particular cognitivedisorders such as mild cognitive disorder (MCI), Alzheimer's disease,Lewy-Body dementia, Parkinson's disease and cerebrovascular dementia;and (5) in cardiac arrhythmias.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the above mentionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to a method for inhibiting PDE,particularly PDE2, comprising contacting said PDE with an effectiveamount of a compound according to the invention.

The invention further relates to a method for inhibiting PDE,particularly PDE2, comprising administering a pharmacologically activeand therapeutically effective and tolerable amount of at least onecompound according to the invention to a mammal in need of suchinhibition.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention further relates to the compounds according to theinvention having PDE, particularly PDE2, inhibitory activity.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of PDE-, particularlyPDE2-, associated diseases.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

The invention moreover relates to pharmaceutical compositions havingPDE, particularly PDE2, inhibitory activity.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective for antagonizing the effects of the cyclicnucleotide phosphodiesterase of type 2 (PDE2), ameliorating the symptomsof an PDE2-mediated disorder, and wherein the packaging materialcomprises a label or package insert which indicates that thepharmaceutical agent is useful for preventing or treating PDE2-mediateddisorders, and wherein said pharmaceutical agent comprises one or morecompounds of formula 1 according to the invention. The packagingmaterial, label and package insert otherwise parallel or resemble whatis generally regarded as standard packaging material, labels and packageinserts for pharmaceuticals having related utilities.

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Intravenous and oral deliveryis preferred.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, caplets,suppositories, patches (e.g. as TTS), emulsions, suspensions, gels orsolutions, the active compound content advantageously being between 0.1and 95% and where, by the appropriate choice of the auxiliaries and/orexcipients, a pharmaceutical administration form (e.g. a delayed releaseform or an enteric form) exactly suited to the active compound and/or tothe desired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of skin diseases, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further processed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for PDE inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarly between0.1 and 3 mg per day. The customary dose in the case of systemic therapy(p.o. or i.v.) is between 0.03 and 3 mg/kg per day.

Biological Investigations

Method for Measuring Inhibition of PDEs Activities

Abbreviations:

PDE: phosphodiesterase, PCR: polymerase chain reaction, RT-PCR: reversetranscription-polymerase chain reaction, dNTPs: deoxynucleosidetriphosphates, RNA: ribonucleic acid, cDNA: complementarydeoxyribonucleic acid, bp: basepairs, (dT)₁₅: pentadecathymidylic acid,ORF: open reading frame, GB no.: GenBank database accession number, rBV:recombinant baculovirus, wt: wild type, aa: aminoacid, UCR: upstreamconserved region, PAA: polyacrylamide.

Aminoacids are abbreviated with the 1-character symbol: A for alanine, Cfor cysteine, D for aspartic acid, E for glutamic acid, F forphenylalanine, G for glycine, H for histidine, I for isoleucine, K forlysine, L for leucine, M for methionine, N for asparagine, P forproline, Q for glutamine, R for arginine, S for serine, T for threonine,V for valine, W for tryptophane, Y for tyrosine.

General Methods for Cloning Recombinant PDEs

RNA was purified from cell lines using the RNeasy Mini Kit from Qiagen.1 μg RNA was reverse transcribed into single-stranded cDNA in a 20 μlreaction using Expand Reverse Transcriptase (Roche) with 50 pM of primer(dT)₁₅ and 1 mM dNTPs (both from Roche). 5 μl of cDNA were used astemplate for the subsequent PCR reaction. Human cDNAs from tissues werepurchased from Clontech or Invitrogen. 1 μl was used for PCR reaction.

PCR was carried out in a Stratagene Robocycler 40 or in a MWG Primus 96plus thermocycler. Typically, PCR was carried out with the Expand LondTemplate PCR System from Roche in buffer 3 plus 0.75 mM MgCl₂, 0.3 μMeach primer, 500 μM dNTPs.

PCR products were purified with the High Pure PCR Product PurificationKit (Roche) or from agarose gel with the QIAquick Gel Extraction kitfrom Qiagen, and cloned into the pCR2.1-TOPO vector from Invitrogen. TheORFs were subcloned in baculovirus expression vectors (transferplasmids). The pCR-Bac and pVL vectors were from Invitrogen. The pBacPakvectors (pBP8 or pBP9) were from Clontech. Restriction endonucleaseswere from Roche and MBI Fermentas. Modifying enzymes and T4 DNA ligasewere from New England Biolabs. DNA was sequenced by the company GATCGmbH (Konstanz, Germany, www.gatc.de) or in ALTANA Pharma's lab using anABI PRISM 310 and the Big dye terminator cycle sequencing v2 chemistry(Applied Biosystem). Sequence analysis was performed with HitachiSoftware DNASIS Version 2.5 or with Vector NTI 7. When necessary, invitro mutagenesis was eventually performed with the QuickChangeSite-Directed Mutagenesis Kit from Stratagene.

Cloning of Human PDE 2A3

The PDE2A3 (GB no. U67733) was amplified in 2 steps using PCR from braincDNA. A N-terminal fragment was isolated using primers CP1PD2AS(5′-GAGGAGTGATGGGGCAGGC-3′) and PR9PD2AA (5′-GCGAAGTGGGAGACAGAAAAG-3′),a C-terminal fragment was isolated using primers PR7PD2AS(5′-GATCCTGAACATCCCTGACG-3′) and CP3PD2AA (5′-GGGATCACTCAGCATCAAGGC-3′).The PCR products were cloned into the vector pCR2.1-Topo. The N-terminalfragment was first subcloned with EcoRI into pBluescript II KS (−),afterwards a Bst1107I/EcoRV fragment was exchanged with thecorresponding restriction fragment from the C-terminal clone, to obtaina complete ORF. The ORF for the PDE2A3 was subcloned into pBP8 usingXbaI and KpnI.

Expression of Recombinant PDE2

The rBV was prepared by means of homologous recombination in Sf9 insectcells. The expression plasmids were cotransfected with Bac-N-Blue(Invitrogen) or Baculo-Gold DNA (Pharmingen) using a standard protocol(Pharmingen). Wt virus-free recombinant virus supernatants were selectedusing plaque assay methods. After that, high-titre virus supernatantswere prepared by amplifying 3 times. PDE2 was expressed in Sf21 cells byinfecting 2×10⁶ cells/ml with an MOI (multiplicity of infection) between1 and 10 in serum-free SF900 medium (Life Technologies). Cells werecultured at 28° C., typically for 48 hours, after which they werepelleted for 5-10 min at 1000 g and 4° C. In spinner flasks, cells werecultured at a rotational speed of 75 rpm. The SF21 insect cells wereresuspended, at a concentration of approx. 10⁷ cells/ml, in ice-cold (4°C.) homogenization buffer (20 mM Tris, pH 8.2, containing the followingadditions: 140 mM NaCl, 3.8 mM KCl, 1 mM EGTA, 1 mM MgCl₂, 1 mMβ-mercaptoethanol, 2 mM benzamidine, 0.4 mM Pefablock, 10 μM leupeptin,10 μM pepstatin A, 5 μM trypsin inhibitor) and disrupted byultrasonication. The homogenate was then centrifuged for 10 min at1000×g and the supernatant was stored at −80° C. until subsequent use(see below). The protein content was determined by the Bradford method(BioRad, Munich) using BSA as standard. Integrity and size ofrecombinant proteins were analysed by western blot.

Measurement of Recombinant Human PDE2A3 Inhibition by SPA Technology

Recombinant human PDE2A3 activities were inhibited by the test samplesin a modified SPA (scintillation proximity assay) test, supplied byAmersham Pharmacia Biotech (see procedural instructions“phosphodiesterase [3H]cAMP SPA enzyme assay, code TRKQ 7090”), carriedout in 96-well microtitre plates (MTP's). The test volume is 100 μl andcontains 20 mM Tris buffer (pH 7.4), 0.1 mg of BSA (bovine serumalbumin)/ml, 5 mM Mg²⁺, 0.5 μM cAMP (including about 50,000 cpm of[3H]cAMP), 5 μM cGMP (to activate PDE2A3), 2 μl of the respectivesubstance dilution in DMSO and sufficient recombinant PDE (1000×gsupernatant, see above) to ensure that 15-20% of the cAMP is convertedunder the said experimental conditions. After a preincubation of 5 minat 37° C., the reaction is started by adding the substrate (cAMP) andthe assays are incubated for a further 15 min; after that, they arestopped by adding SPA beads (50 μl). In accordance with themanufacturer's instructions, the SPA beads had previously beenresuspended in water and then diluted 1:3 (v/v); the diluted solutionalso contains 3 mM IBMX. After the beads have been sedimented (>30 min),the MTP's are analyzed in commercially available measuring appliancesand the corresponding IC₅₀ values of the compounds for the inhibition ofPDE activities are determined from the concentration-effect curves bymeans of non-linear regression.

Method to Assess Inhibition of Macromolecule Permeability of HUVECMonolayers

The procedure to measure macromolecule permeability of endothelial cellmonolayers followed the method described by Langeler & van Hinsbergh(1988) with modifications. Human umbilical vein endothelial cells wereisolated from umbilical cords according to standard procedures (Jaffe etal. 1973) and cultured in endothelial cell basal medium (EBM)supplemented with 2% FCS, 0.5 ng/ml VEGF, 10 ng/ml bFGF, 5 ng/ml EGF, 20ng/ml Long R3 IGF-1, 0.2 μg/ml hydrocortisone, 1 μg/ml ascorbic acid,22.5 μg/ml heparin, 50 μg/ml gentamicin, 50 ng/ml amphotericin B (EGM2purchased from Promocell GmbH, Heidelberg, Germany). At confluency,cells were trypsinized and replated at 73000 cells per well on 3 μmpolycarbonate filter Transwell inserts (Costar GmbH, Bodenheim, Germany)precoated with 10 μg cm²⁻¹ Fibronectin (Sigma, Taufkirchen, Germany).HUVECs were cultured in EGM2 (100 μl in the upper wells and 600 μl inthe lower wells) over four days prior the experiments and medium waschanged every other day. At the day of the experiment culture medium wasreplaced by M199 with 1% human serum albumin. Endothelial cells werepreincubated with cyclic nucleotide modifiers (the selective PDE3inhibitor motapizone, the selective PDE4 inhibitor RP73401, the cGMPgenerators ANP or SNP and PDE2 inhibitors) for 15 min. HUVECs were thenstimulated with Thrombin (1 U ml⁻¹) (Sigma, Taufkichen, Germany) andhorsh radish peroxidase (5 μg/ml) (Sigma, Taufkirchen, Germany) as themacromolecule marker protein was added to the upper wells. Following 1 hincubation time Transwells were removed and the activity of horsh radishperoxidase that penetrated the endothelial cell monolayer was measuredin the lower wells with the 3,3′, 5,5′-tetramethylbenzidine liquidsubstrate system from Sigma (Taufkirchen, Germany).

Results

Representative inhibitory values [measured as −log IC₅₀ (mol/l)]determined in the aforementioned assay follow from the following tableA, in which the numbers of the compounds correspond to the numbers ofthe examples.

TABLE A Inhibition of PDE2 activity Compound -log IC₅₀ [mol/l] 1 to 66,and 75 to The inhibitory values of 110, and 112, these listed compoundsand 116-118 lie in the range from 7.5 to 9.2.

In parallel, compounds according to the invention can inhibitThrombin-induced permeability of HUVEC monolayers for horsh radishperoxidase (HRP) as a macromolecule marker. Therefore, PDE2 inhibitorsare suggested to improve the endothelial barrier function, which isimpaired in numerous conditions such as acute respiratory distresssyndrome (ARDS) or severe pneumonia. The system to measure thesecellular effects of the PDE2 inhibitors observed the enzymologicalcharacteristics of PDE2 which exhibits a rather high Km for cAMP and theactivity of which is activated by cGMP. The Thrombin-induced increase ofHRP permeability was completely abolished by complete inhibition of PDE3(10 μM Motapizone) and PDE4 (1 μM RP73401). However, in the additionalpresence of ANP (100 nM) or SNP (1 mM) to augment cGMP the inhibition byPDE3 and 4 inhibition of permeability was partially reversed. PDE2inhibitors blocked the thrombin-stimulated HRP-permeability if 1 μMRP73401, 10 μM Motapizone, 100 nM ANP or 1 mM SNP were presentindicating that ANP or SNP by generating cGMP activate PDE2. Theconcentration-dependent inhibition of HRP permeability at differentconcentrations was assessed from the percent inhibition in the presenceand absence of the PDE2 inhibitors and in the presence of 1 μM RP73401,10 μM Motapizone and 100 nM ANP. In the absence of PDE3 and 4inhibition, ANP or SNP the PDE2 inhibitors showed very little effect inThrombin-induced macromolecule hyperpermeability.

Inhibition of SNP- or ANP-Induced Permeability of HUVEC Monolayers:

HUVEC cells on 3 μm polycarbonate filters (Transwells) were preincubatedwith 1 μM RP73401 (to block PDE4) and 10 μM Motapizone (to block PDE3),1 mM SNP or 100 nM ANP and 1 μM of test sample over 15 min and thenstimulated with 1 U/ml thrombin. HRP passage into the lower wells wasassessed after 60 min. RP73401 and Motapizone completely blockedthrombin-induced hyperpermeability, which was partially reversed by SNPand ANP.

Compounds according to this invention can inhibit the SNP- orANP-induced permeability increase in a concentration-dependent fashion.

Representative inhibitory values [measured as −log IC₅₀ (mol/l)]determined in the aforementioned assay follow from the following tableB, in which the numbers of the compounds correspond to the numbers ofthe examples.

TABLE B Inhibition of SNP- or ANP-induced permeability Compound -logIC₅₀ [mol/l] 3, 4, 5, 7, 8, 11, The inhibitory values of 12, 17, 18, 21,these listed compounds 25, 30, 38, 54 lie in the range from 7.2 and 85to 8.7.

1-14. (canceled)
 15. A method for treating pneumonia or acuterespiratory distress syndrome (ARDS) in septic shock in a patient inneed thereof, comprising administering to said patient a therapeuticallyeffective amount of a compound of formula I

in which R1 is —U-A, in which U is a direct bond, or methylene (—CH₂—),A is phenyl, pyridinyl, thiophenyl, or R11- and/or R111-substitutedphenyl, in which R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino,di-1-4C-alkylamino, or completely or predominantly fluorine-substituted1-4C-alkoxy, R111 is 1-4C-alkoxy, halogen, hydroxyl, or 1-4C-alkyl, R2is amino, carboxyl, 1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5,in which R3 is 1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl,trifluoromethyl, phenyl, R31- and/or R311-substituted phenyl, furanyl,imidazol-4-yl, pyridinyl, R32-substituted 1-4C-alkyl, or1N—(R33)-piperidinyl, in which R31 is 1-4C-alkoxy, halogen, nitro,1-4C-alkyl, trifluoromethyl, hydroxyl, 1-4C-alkoxycarbonyl,3-7C-cyloalkylmethoxy, morpholino, or mono- or di-1-4C-alkylamino, R311is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or 3-7C-cyloalkylmethoxy,or R31 and R311 together are a 1-2C-alkylenedioxy group, R32 ishydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321- and/orR3211-substituted phenyl, mono- or di-1-4C-alkylamino, morpholino, or4N—(R322)-piperazin-1-yl, in which R321 is 1-4C-alkoxy, halogen, nitro,1-4C-alkyl, trifluoromethyl, hydroxyl, 1-4C-alkoxycarbonyl,3-7C-cyloalkylmethoxy, or mono- or di-1-4C-alkylamino, R3211 is1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or 3-7C-cyloalkylmethoxy, orR321 and R3211 together are a 1-2C-alkylenedioxy group, R322 is1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or 1-4C-alkylcarbonyl, R4 ishydrogen, 1-4C-alkyl, R41-substituted 2-4C-alkyl, phenyl, R42- and/orR421-substituted phenyl, or pyridinyl, in which R41 is hydroxyl,1-4C-alkoxy, mono- or di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl, hydroxyl,1-4C-alkoxycarbonyl, 3-7C-cyloalkylmethoxy, or mono- ordi-1-4C-alkylamino, R421 is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl,or 3-7C-cyloalkylmethoxy, or R42 and R421 together are a1-2C-alkylenedioxy group, R5 is hydrogen, or 1-4C-alkyl, or R4 and R5together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof.
 16. The method according to claim 15, in whichR1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), A isphenyl, pyridinyl, thiophenyl, di-(1-4C-alkoxy)-phenyl, orR11-substituted phenyl, in which R11 is 1-4C-alkyl, halogen,trifluoromethyl, hydroxyl, 1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl,morpholino, di-1-4C-alkylamino, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is amino, carboxyl,1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-4C-alkyl, or 1N—(R33)-piperidinyl, in which R31 is1-4C-alkoxy, morpholino, or di-1-4C-alkylamino, R32 is hydroxyl,phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321-substituted phenyl,di-1-4C-alkylamino, morpholino, or 4N—(R322)-piperazin-1-yl, in whichR321 is 1-4C-alkoxy, R322 is 1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or1-4C-alkylcarbonyl, R4 is hydrogen, 1-4C-alkyl, R41-substituted2-4C-alkyl, phenyl, R42-substituted phenyl, or pyridinyl, in which R41is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, or di-1-4C-alkylamino, R5 is hydrogen, or 1-4C-alkyl, or R4and R5 together and with inclusion of the nitrogen atom, to which theyare bonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof.
 17. The method according to claim 15, in whichR1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), A isphenyl, pyridinyl, thiophenyl, dimethoxyphenyl, or R11-substitutedphenyl, in which R11 is methyl, tertbutyl, chlorine, fluorine, bromine,trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, phenoxy,methoxycarbonyl, morpholino, or dimethylamino, R2 is amino, carboxyl,1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-4C-alkyl, or 1N—(R33)-piperidinyl, in which R31 is1-4C-alkoxy, morpholino, or di-1-4C-alkylamino, R32 is hydroxyl,phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321-substituted phenyl,di-1-4C-alkylamino, morpholino, or 4N—(R322)-piperazin-1-yl, in whichR321 is 1-4C-alkoxy, R322 is 1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or1-4C-alkylcarbonyl, R4 is hydrogen, 1-4C-alkyl, R41-substituted2-4C-alkyl, phenyl, R42-substituted phenyl, or pyridinyl, in which R41is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, or di-1-4C-alkylamino, R5 is hydrogen, or 1-4C-alkyl, or R4and R5 together and with inclusion of the nitrogen atom, to which theyare bonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof.
 18. The method according to claim 15, in whichR1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), A isphenyl, or R11-substituted phenyl, in which R11 is methyl, chlorine,fluorine, bromine, trifluoromethyl, hydroxyl, methoxy, phenoxy,methoxycarbonyl, or dimethylamino, R2 is amino, carboxyl,methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is methyl,vinyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, R31-substitutedphenyl, furanyl, imidazol-4-yl, pyridinyl, R32-substituted 1-2C-alkyl,or 1N—(R33)-piperidinyl, in which R31 is methoxy, morpholino, ordimethylamino, R32 is hydroxyl, benzyloxy, methoxy, phenyl,R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino, or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, or 4N-methyl-piperazin-1-yl, ora pharmaceutically acceptable salt thereof.
 19. The method according toclaim 15, in which R1 is —U-A, in which U is a direct bond, A is phenyl,or R11-substituted phenyl, in which R11 is fluorine, bromine,trifluoromethyl, or methoxy, R2 is attached in the meta or para positionwith respect to the binding position in which the phenyl ring is bondedto the amino group of the triazolophthalazine scaffold, and is amino,carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl, in which R31 ismethoxy, morpholino, or dimethylamino, R32 is hydroxyl, benzyloxy,methoxy, phenyl, R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino, or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, or 4N-methyl-piperazin-1-yl, ora pharmaceutically acceptable salt thereof.
 20. The method according toclaim 15, in which R1 is —U-A, in which U is a direct bond, A is phenyl,or R11-substituted phenyl, in which R11 is fluorine, bromine, chlorine,trifluoromethyl, methyl or methoxy, R2 is attached in the meta or paraposition with respect to the binding position in which the phenyl ringis bonded to the amino group of the triazolophthalazine scaffold, and isamino, carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, inwhich R3 is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl,phenyl, R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl, in which R31 ismethoxy, morpholino, or dimethylamino, R32 is hydroxyl, benzyloxy,methoxy, phenyl, R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, 4N-methyl-piperazin-1-yl, or4N-ethyl-piperazin-1-yl, or a pharmaceutically acceptable salt thereof.21. The method according to claim 15, in which R1 is 4-methoxy-phenyl,2-methoxy-phenyl, 2-bromo-phenyl, 2-fluoro-phenyl,2-(trifluoromethyl)-phenyl, 2-chloro-phenyl, 4-bromo-phenyl or2-methyl-phenyl, or a pharmaceutically acceptable salt thereof.
 22. Themethod according to claim 15, wherein the compound of formula I isselected from the group consisting of Cyclopropanecarboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide,Cyclopropanecarboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide,and1-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-methanone.23. A method for treating acute or chronic airway disorders in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of a compound of formula I

in which R1 is —U-A, in which U is a direct bond, or methylene (—CH₂—),A is phenyl, pyridinyl, thiophenyl, or R11- and/or R111-substitutedphenyl, in which R11 is 1-4C-alkyl, halogen, trifluoromethyl, hydroxyl,1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl, morpholino,di-1-4C-alkylamino, or completely or predominantly fluorine-substituted1-4C-alkoxy, R111 is 1-4C-alkoxy, halogen, hydroxyl, or 1-4C-alkyl, R2is amino, carboxyl, 1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5,in which R3 is 1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl,trifluoromethyl, phenyl, R31- and/or R311-substituted phenyl, furanyl,imidazol-4-yl, pyridinyl, R32-substituted 1-4C-alkyl, or 1N—(R33)-piperidinyl, in which R31 is 1-4C-alkoxy, halogen, nitro,1-4C-alkyl, trifluoromethyl, hydroxyl, 1-4C-alkoxycarbonyl,3-7C-cyloalkylmethoxy, morpholino, or mono- or di-1-4C-alkylamino, R311is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or 3-7C-cyloalkylmethoxy,or R31 and R311 together are a 1-2C-alkylenedioxy group, R32 ishydroxyl, phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321- and/orR3211-substituted phenyl, mono- or di-1-4C-alkylamino, morpholino, or4N—(R322)-piperazin-1-yl, in which R321 is 1-4C-alkoxy, halogen, nitro,1-4C-alkyl, trifluoromethyl, hydroxyl, 1-4C-alkoxycarbonyl,3-7C-cyloalkylmethoxy, or mono- or di-1-4C-alkylamino, R3211 is1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl, or 3-7C-cyloalkylmethoxy, orR321 and R3211 together are a 1-2C-alkylenedioxy group, R322 is1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or 1-4C-alkylcarbonyl, R4 ishydrogen, 1-4C-alkyl, R41-substituted 2-4C-alkyl, phenyl, R42- and/orR421-substituted phenyl, or pyridinyl, in which R41 is hydroxyl,1-4C-alkoxy, mono- or di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, halogen, nitro, 1-4C-alkyl, trifluoromethyl, hydroxyl,1-4C-alkoxycarbonyl, 3-7C-cyloalkylmethoxy, or mono- ordi-1-4C-alkylamino, R421 is 1-4C-alkoxy, halogen, 1-4C-alkyl, hydroxyl,or 3-7C-cyloalkylmethoxy, or R42 and R421 together are a1-2C-alkylenedioxy group, R5 is hydrogen, or 1-4C-alkyl, or R4 and R5together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof, wherein the acute or chronic airway disorder isselected from the group consisting of rhinitis, bronchitis, bronchialasthma, emphysema and COPD.
 24. The method according to claim 23, inwhich R1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), Ais phenyl, pyridinyl, thiophenyl, di-(1-4C-alkoxy)-phenyl, orR11-substituted phenyl, in which R11 is 1-4C-alkyl, halogen,trifluoromethyl, hydroxyl, 1-4C-alkoxy, phenoxy, 1-4C-alkoxycarbonyl,morpholino, di-1-4C-alkylamino, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, R2 is amino, carboxyl,1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-4C-alkyl, or 1N—(R33)-piperidinyl, in which R31 is1-4C-alkoxy, morpholino, or di-1-4C-alkylamino, R32 is hydroxyl,phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321-substituted phenyl,di-1-4C-alkylamino, morpholino, or 4N—(R322)-piperazin-1-yl, in whichR321 is 1-4C-alkoxy, R322 is 1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or1-4C-alkylcarbonyl, R4 is hydrogen, 1-4C-alkyl, R41-substituted2-4C-alkyl, phenyl, R42-substituted phenyl, or pyridinyl, in which R41is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, or di-1-4C-alkylamino, R5 is hydrogen, or 1-4C-alkyl, or R4and R5 together and with inclusion of the nitrogen atom, to which theyare bonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof.
 25. The method according to claim 23, in whichR1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), A isphenyl, pyridinyl, thiophenyl, dimethoxyphenyl, or R11-substitutedphenyl, in which R11 is methyl, tertbutyl, chlorine, fluorine, bromine,trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, phenoxy,methoxycarbonyl, morpholino, or dimethylamino, R2 is amino, carboxyl,1-4C-alkoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is1-4C-alkyl, 2-4C-alkenyl, 3-7C-cycloalkyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-4C-alkyl, or 1N—(R33)-piperidinyl, in which R31 is1-4C-alkoxy, morpholino, or di-1-4C-alkylamino, R32 is hydroxyl,phenyl-1-4C-alkoxy, 1-4C-alkoxy, phenyl, R321-substituted phenyl,di-1-4C-alkylamino, morpholino, or 4N—(R322)-piperazin-1-yl, in whichR321 is 1-4C-alkoxy, R322 is 1-4C-alkyl, R33 is hydrogen, 1-4C-alkyl, or1-4C-alkylcarbonyl, R4 is hydrogen, 1-4C-alkyl, R41-substituted2-4C-alkyl, phenyl, R42-substituted phenyl, or pyridinyl, in which R41is hydroxyl, 1-4C-alkoxy, di-1-4C-alkylamino, or morpholino, R42 is1-4C-alkoxy, or di-1-4C-alkylamino, R5 is hydrogen, or 1-4C-alkyl, or R4and R5 together and with inclusion of the nitrogen atom, to which theyare bonded, form a heterocyclic ring radical Het, in which Het ismorpholino, or 4N-(1-4C-alkyl)-piperazin-1-yl, or a pharmaceuticallyacceptable salt thereof.
 26. The method according to claim 23, in whichR1 is —U-A, in which U is a direct bond, or methylene (—CH₂—), A isphenyl, or R11-substituted phenyl, in which R11 is methyl, chlorine,fluorine, bromine, trifluoromethyl, hydroxyl, methoxy, phenoxy,methoxycarbonyl, or dimethylamino, R2 is amino, carboxyl,methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3 is methyl,vinyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl, R31-substitutedphenyl, furanyl, imidazol-4-yl, pyridinyl, R32-substituted 1-2C-alkyl,or 1N—(R33)-piperidinyl, in which R31 is methoxy, morpholino, ordimethylamino, R32 is hydroxyl, benzyloxy, methoxy, phenyl,R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino, or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, or 4N-methyl-piperazin-1-yl, ora pharmaceutically acceptable salt thereof.
 27. The method according toclaim 23, in which R1 is —U-A, in which U is a direct bond, A is phenyl,or R11-substituted phenyl, in which R11 is fluorine, bromine,trifluoromethyl, or methoxy, R2 is attached in the meta or para positionwith respect to the binding position in which the phenyl ring is bondedto the amino group of the triazolophthalazine scaffold, and is amino,carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, in which R3is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl, phenyl,R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl, in which R31 ismethoxy, morpholino, or dimethylamino, R32 is hydroxyl, benzyloxy,methoxy, phenyl, R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino, or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, or 4N-methyl-piperazin-1-yl, ora pharmaceutically acceptable salt thereof.
 28. The method according toclaim 23, in which R1 is —U-A, in which U is a direct bond, A is phenyl,or R11-substituted phenyl, in which R11 is fluorine, bromine, chlorine,trifluoromethyl, methyl or methoxy, R2 is attached in the meta or paraposition with respect to the binding position in which the phenyl ringis bonded to the amino group of the triazolophthalazine scaffold, and isamino, carboxyl, methoxycarbonyl, —N(H)—C(O)R3, or —C(O)—N(R4)R5, inwhich R3 is methyl, vinyl, cyclopropyl, cyclohexyl, trifluoromethyl,phenyl, R31-substituted phenyl, furanyl, imidazol-4-yl, pyridinyl,R32-substituted 1-2C-alkyl, or 1N—(R33)-piperidinyl, in which R31 ismethoxy, morpholino, or dimethylamino, R32 is hydroxyl, benzyloxy,methoxy, phenyl, R321-substituted phenyl, dimethylamino, morpholino, or4N-methyl-piperazin-1-yl, in which R321 is methoxy, R33 is hydrogen,methyl, or acetyl, R4 is hydrogen, methyl, 2-(R41)-ethyl, phenyl,R42-substituted phenyl, or pyridinyl, in which R41 is hydroxyl, methoxy,dimethylamino or morpholino, R42 is methoxy, or dimethylamino, R5 ishydrogen, or methyl, or R4 and R5 together and with inclusion of thenitrogen atom, to which they are bonded, form a heterocyclic ringradical Het, in which Het is morpholino, 4N-methyl-piperazin-1-yl, or4N-ethyl-piperazin-1-yl, or a pharmaceutically acceptable salt thereof.29. The method according to claim 23, in which R1 is 4-methoxy-phenyl,2-methoxy-phenyl, 2-bromo-phenyl, 2-fluoro-phenyl,2-(trifluoromethyl)-phenyl, 2-chloro-phenyl, 4-bromo-phenyl or2-methyl-phenyl, or a pharmaceutically acceptable salt thereof.
 30. Themethod according to claim 23, wherein the compound of formula I isselected from the group consisting of Cyclopropanecarboxylic acid{4-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide,Cyclopropanecarboxylic acid{3-[3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-amide,and1-{4-[3-(4-Methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazin-6-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-methanone.